The present invention relates to new disubstituted bicyclic heterocycles of general formula
Raxe2x80x94Axe2x80x94Hetxe2x80x94Bxe2x80x94Arxe2x80x94Exe2x80x83xe2x80x83(I)
the tautomers, stereoisomers and mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases which have valuable properties.
The compounds of general formula I above wherein E denotes a cyano group are valuable intermediates for preparing the other compounds of general formula I, and the compounds of general formula I above wherein E denotes an RbNHxe2x80x94C(xe2x95x90NH)xe2x80x94 group, and the tautomers and stereoisomers thereof have useful pharmacological properties, particularly a thrombin-inhibiting activity and the effect of extending thrombin time.
The present application thus relates to the new compounds of general formula I above and the preparation thereof, pharmaceutical compositions containing the pharmacologically active compounds and the use thereof.
In the above general formula:
A denotes a carbonyl or sulfonyl group linked to the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the group Het, whilst moreover the abovementioned moieties may not contain an R1 group,
B denotes an ethylene group, wherein a methylene group, linked either to the group Het or Ar, may be replaced by an oxygen or sulfur atom or by a sulfinyl, sulfonyl, carbonyl or xe2x80x94NR1 group, wherein
R1 denotes a hydrogen atom or a C1-6-alkyl group,
E denotes a cyano or RbNHxe2x80x94C(xe2x95x90NH)xe2x80x94 group wherein
Rb denotes a hydrogen atom, a hydroxy group, a C1-3-alkyl group or a group which may be cleaved in vivo,
Ar denotes a phenylene or naphthylene group optionally substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl, C1-3-alkyl, or C1-3-alkoxy group,
a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C1-3-alkyl group,
Het denotes a bicyclic heterocycle of formula 
X is a nitrogen atom and
Y is an oxygen or sulfur atom or a nitrogen atom optionally substituted by a C1-6-alkyl or C3-7-cycloalkyl group, whilst additionally one or two non-angular methyne groups in the phenyl moiety of the above-mentioned bicyclic heterocycle may each be replaced by a nitrogen atom,
or X denotes a methyne group optionally substituted by the group R1, wherein R1 is as hereinbefore defined, and
Y denotes a nitrogen atom optionally substituted by a C1-6-alkyl or C3-7-cycloalkyl group,
or Het denotes a group of the formula 
R1 is as hereinbefore defined,
Z denotes an oxygen or sulfur atom,
one of the groups D or G denotes a nitrogen atom and the other group D or G denotes a methyne group,
and Ra denotes a C1-6-alkyl group, a C3-7-cycloalkyl group optionally substituted by a C1-3-alkyl group, wherein the C1-3-alkyl group may additionally be substituted by a carboxyl group or by a group which may be converted in vivo into a carboxy group,
or an R2NR3xe2x80x94 group wherein
R2 denotes a C1-4-alkyl group, which may be substituted by a carboxy, C1-6-alkyloxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl or 1H-tetrazolyl group,
a C2-4-alkyl group substituted by a hydroxy, phenyl-C1-3-alkoxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the xcex1-position relative to the adjacent nitrogen atom may not be substituted, or
a piperidinyl group optionally substituted by a C1-3-alkyl group and
R3 denotes a hydrogen atom, a C3-6-alkyl group, a C3-7-cycloalkyl group optionally substituted by a C1-3-alkyl group, a C3-6-alkenyl or alkynyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R2NR3xe2x80x94 group,
a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C1-3-alkyl or C1-3-alkoxy group, a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl or imidazolyl group or
R2 and R3 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxymethyl or C1-4-alkoxycarbonyl group, onto which a phenyl ring may additionally be fused.
The compounds of the above general formula I which contain a group capable of being cleaved in vivo are thus prodrugs and compounds of general formula I which contain two groups capable of being cleaved in vivo are so-called double prodrugs.
The phrase xe2x80x9ca group which may be converted in vivo into a carboxy groupxe2x80x9d denotes, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic moiety is preferably a C1-6-alkanol, a phenyl-C1-3-alkanol, a C3-9-cycloalkanol, wherein a C5-8-cycloalkanol may additionally be substituted by one or two C1-3-alkyl groups, a C5-8-cycloalkanol, in which a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl-C1-3-alkoxycarbonyl or C2-6-alkanoyl group, and the cycloalkanol moiety may additionally be substituted by one or two C1-3-alkyl groups, a C4-7-cycloalkenol, a C3-5-alkenol, a phenyl-C3-5-alkenol, a C3-5-alkynol or phenyl-C3-5-alkynol, with the proviso that no bond to the oxygen atom emanates from a carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-C1-3-alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms, which may additionally be substituted in the bicycloalkyl moiety by one or two C1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula
R4xe2x80x94COxe2x80x94Oxe2x80x94(R5CR6)xe2x80x94OH,
wherein:
R4 denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group;
R5 denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl, or phenyl group; and
R6 denotes a hydrogen atom or a C1-3-alkyl group,
or the phrase xe2x80x9ca group which may be cleaved in vivo from an imino or amino groupxe2x80x9d denotes for example a hydroxy group, an acyl group such as a benzoyl or pyridinoyl group or a C1-6-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1-6-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1-6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C1-3-alkylsulfonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl or R4COxe2x80x94Oxe2x80x94(R5CR6)xe2x80x94Oxe2x80x94COxe2x80x94 group, wherein R4 to R6 are as hereinbefore defined.
Examples of preferred prodrug groups for a carboxy group include a C1-6-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, or cyclohexyloxycarbonyl group or phenyl-C1-3-alkoxycarbonyl group such as the benzyloxycarbonyl group and
for an imino or amino group a C1-9-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a phenyl-C1-3-alkoxycarbonyl group such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a C1-3-alkyl group such as the benzoyl or 4-ethylbenzoyl group, a pyridinoyl group such as the nicotinoyl group, a C1-3-alkylsulfonyl-n-C2-3-alkoxycarbonyl or C1-3-alkoxy-C2-3-alkoxy-C2-4-alkoxycarbonyl group such as the 2-methylsulfonylethoxycarbonyl or 2-(2-ethoxy)ethoxycarbonyl group.
Moreover, the saturated alkyl and alkoxy moieties containing more than 2 carbon atoms as well as alkanoyl and unsaturated alkyl moieties containing more than 3 carbon atoms as mentioned in the foregoing definitions also include the branched isomers thereof such as for example the isopropyl, tert-butyl and isobutyl group, etc.
Preferred compounds of the above general formula I, however, are those wherein:
A denotes a carbonyl or sulfonyl group linked to the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the group Het, whilst moreover the abovementioned moieties may not contain an R1 group,
B denotes an ethylene group, in which a methylene group, linked either to the group Het or Ar, may be replaced by an oxygen or sulfur atom or by a sulfinyl, sulfonyl, carbonyl or xe2x80x94NR1xe2x80x94 group, wherein
R1 denotes a hydrogen atom or a C1-5-alkyl group,
E denotes an RbNHxe2x80x94C(xe2x95x90NH)xe2x80x94 group wherein
Rb denotes a hydrogen atom, a hydroxy group, a C1-3-alkyl group or a group which may be cleaved in vivo,
Ar denotes a phenylene group optionally substituted by a fluorine, chlorine or bromine atom or by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group,
a thienylene, thiazolylene, pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group optionally substituted in the carbon skeleton by a C1-3-alkyl group,
Het denotes a bicyclic heterocycle of formula 
X is a nitrogen atom and
Y is an oxygen or sulfur atom or a nitrogen atom optionally substituted by a C1-6-alkyl or C3-7-cycloalkyl group, whilst additionally one or two non-angular methyne groups in the phenyl moiety of the above-mentioned bicyclic heterocycle may each be replaced by a nitrogen atom,
or X denotes a methyne group optionally substituted by the group R1, wherein R1 is as hereinbefore defined, and
Y denotes a nitrogen atom optionally substituted by a C1-6-alkyl or C3-7-cycloalkyl group,
or Het denotes a group of the formulae 
R1 is as hereinbefore defined,
Z denotes an oxygen or sulfur atom,
one of the groups D or G denotes a nitrogen atom and the other group D or G denotes a methyne group,
and Ra denotes a C1-6-alkyl group, a C3-7-cycloalkyl group optionally substituted by a C1-3-alkyl group, wherein the C1-3-alkyl group may additionally be substituted by a carboxyl group or by a group which may be converted in vivo into a carboxy group,
or a R2NR3xe2x80x94 group wherein
R2 denotes a C1-4-alkyl group, which may be substituted by a carboxy, C1-6-alkyloxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, trifluorosulfonylamino, trifluorosulfonylaminocarbonyl or 1H-tetrazolyl group,
a C2-4-alkyl group substituted by a hydroxy, phenyl-C1-3-alkoxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino or N-(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the xcex1-position relative to the adjacent nitrogen atom may not be substituted, or
a piperidinyl group optionally substituted by a C1-3-alkyl group and
R3 denotes a hydrogen atom, a C1-6-alkyl group, a C3-7-cycloalkyl group optionally substituted by a C1-3-alkyl group, a C3-6-alkenyl or alkynyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R2NR3xe2x80x94 group,
a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a C1-3-alkyl or C1-3-alkoxy group, a benzyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl or piperidinyl group or
R2 and R3 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxy or C1-4-alkoxycarbonyl group, onto which a phenyl ring may additionally be fused, particularly those compounds wherein
Het denotes one of the abovementioned benzimidazolylene, benzothiazolylene, benzoxazolylene, indolylene, quinazolinylene, quinoxazolinonylene, imidazo[4,5-b]pyridinylene, imidazo-[1,2-a]pyridinylene, thiazolo[5,4-b]pyridinylene or thieno[2,3-d]imidazolylene groups, the tautomers, the prodrugs, the double prodrugs, the stereoisomers and the salts thereof.
Particularly preferred compounds of general formula I above are those wherein
A denotes a carbonyl or sulfonyl group linked to the benzo, pyrido, pyrimido, pyrazino, pyridazino or thieno moiety of the group Het, whilst moreover the abovementioned moieties may not contain an R1 group,
B denotes an ethylene group in which the methylene group linked to the group Ar may be replaced by an oxygen or sulfur atom or by an xe2x80x94NR1xe2x80x94 group, wherein
R1 denotes a hydrogen atom or a C1-4-alkyl group,
E denotes an RbNHxe2x80x94C(xe2x95x90NH)xe2x80x94 group wherein
Rb denotes a hydrogen atom, a hydroxy, C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1-3-alkoxycarbonyl, benzoyl, p-C1-3-alkyl-benzoyl or pyridinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-alkoxycarbonyl group may additionally be substituted by a C1-3-alkylsulfonyl or 2-(C1-3-alkoxy)ethyl group,
Ar denotes a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl or methoxy group or it denotes a 2,5-thienylene group,
Het denotes a 1-(C1-3-alkyl)-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-(C1-3-alkyl)-2,5-indolylene, 1-(C1-3-alkyl)-2,5-imidazo[4,5-b]pyridinylene 3-(C1-3-alkyl)-2,7-imidazo[1,2-a]pyridinylene, or 1-(C1-3-alkyl)-2,5-thieno[2,3-d]imidazolylene group, and
Ra denotes an R2NR3xe2x80x94 group wherein
R2 is a C1-4-alkyl group substituted by a carboxy, C1-6-alkyloxycarbonyl, benzyloxycarbonyl, C1-3-alkylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group,
a C2-4-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the xcex1-position to the adjacent nitrogen atom may not be substituted,
R3 denotes a C3-7-cycloalkyl group, a propargyl group, wherein the unsaturated part may not be linked directly to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group, a pyrazolyl, pyridazolyl or pyridinyl group optionally substituted by a methyl group or
R2 and R3 together with the nitrogen atom between them denote a 5- to 7-membered cycloalkyleneimino group, optionally substituted by a carboxy or C1-4-alkoxycarbonyl group, to which a phenyl ring may additionally be fused,
the tautomers, the stereoisomers and the salts thereof.
Most particularly preferred compounds of the above general formula I are those wherein
A denotes a carbonyl or sulfonyl group linked to the benzo, pyrido, or thieno moiety of the group Het, whilst moreover the abovementioned moieties may not contain an R1 group,
B denotes an ethylene group in which the methylene group linked to the group Ar may be replaced by an oxygen or sulfur atom or by an xe2x80x94NR1xe2x80x94 group, wherein
R1 denotes a hydrogen atom or a methyl group,
E denotes an RbNHxe2x80x94C(xe2x95x90NH)xe2x80x94 group, wherein
Rb denotes a hydrogen atom or a hydroxy, C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C1-3-alkylbenzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-alkoxycarbonyl group may additionally be substituted by a C1-3-alkylsulfonyl or 2-(C1-3-alkoxy)ethyl group,
Ar denotes a 1,4-phenylene group optionally substituted by a chlorine atom or by a methyl, ethyl or methoxy group, or it denotes a 2,5-thienylene group,
Het denotes a 1-methyl-2,5-benzimidazolylene, 1-cyclopropyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, 1-methyl-2,5-imidazo[4,5-b]pyridinylene, 3-methyl-2,7-imidazo[1,2-a]pyridinylene or 1-methyl-2,5-thieno[2,3-d]imidazolylene group and
Ra denotes a R2NR3xe2x80x94 group wherein
R2 denotes a C1-3-alkyl group which may be substituted by a carboxy, C1-6-alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl, or 1H-tetrazol-5-yl group,
a C1-3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino, or Nxe2x80x94(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the xcex1-position to the adjacent nitrogen atom may not be substituted, and
R3 denotes a propargyl group, wherein the unsaturated moiety may not be linked directly to the nitrogen atom of the R2NR3 group, a phenyl group optionally substituted by a fluorine or chlorine atom, or by a methyl or methoxy group, or denotes a pyridinyl group,
particularly those wherein
A denotes a carbonyl group linked to the benzo or thieno moiety of the group Het,
B denotes an ethylene group wherein the methylene group attached to the group Ar may be replaced by an xe2x80x94NR1 group, wherein
R1 denotes a hydrogen atom or a methyl group,
E denotes an RbNHxe2x80x94C(xe2x95x90NH)xe2x80x94 group wherein
Rb is a hydrogen atom, a hydroxy, C1-9-alkoxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, benzoyl, p-C1-3-alkylbenzoyl or nicotinoyl group, whilst the ethoxy moiety in the 2-position of the abovementioned C1-9-alkoxycarbonyl group may additionally be substituted by a methylsulfonyl or 2-ethoxyethyl group,
Ar denotes a 1,4-phenylene group optionally substituted by a methoxy group, or denotes a 2,5-thienylene group,
Het denotes a 1-methyl-2,5-benzimidazolylene, 2,5-benzothiazolylene, 1-methyl-2,5-indolylene, or 1-methyl-2,5-thieno[2,3-d]imidazolylene group and
Ra denotes an R2NR3xe2x80x94 group wherein
R2 denotes a C1-3-alkyl group which may be substituted by a carboxy, C1-6-alkyloxycarbonyl, benzyloxycarbonyl, methylsulfonylaminocarbonyl or 1H-tetrazol-5-yl group,
a C2-3-alkyl group substituted by a hydroxy, benzyloxy, carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino group, whilst in the abovementioned groups the carbon atom in the xcex1-position to the adjacent nitrogen atom may not be substituted, and
R3 denotes a phenyl group optionally substituted by a fluorine atom, or denotes a 2-pyridinyl group,
the tautomers, stereoisomers and the salts thereof.
The following are mentioned as examples of particularly preferred compounds:
(a) 2-[N-(4-amidinophenyl)aminomethyl]benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)amide,
(b) 2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzthiazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide,
(c) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide,
(d) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)amide,
(e) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)amide,
(f) 1-Methyl-2-[2-(2-amidinothiophen-5-yl)ethyl]benzimidazol-5-y-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)amide,
(g) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)amide,
(h) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)amide,
(i) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide,
(j) 1-Methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]amide,
(k) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]amide,
(l) 1-Methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)amide,
(m) 1-Methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-hydroxycarbonylethyl)amide,
(n) 1-Methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide,
(o) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[(N-hydroxycarbonylethyl-N-methyl)-2-aminoethyl]amide,
(p) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-hydroxycarbonylethyl)amide,
(q) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-hydroxycarbonylethyl)amide,
(r) 1-Methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide,
(s) 1-Methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)amide,
(t) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]indol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide, and
(u) 1-Methyl-2-[N-(4-amidinophenyl)aminomethyl]thieno[2.3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide,
the tautomers, prodrugs, double prodrugs, stereoisomers and the salts thereof.
The new compounds may be prepared by methods known per se, for example by the following methods:
a. In order to prepare a compound of general formula I, wherein E denotes an RbNHxe2x80x94C(xe2x95x90NH)xe2x80x94 group, wherein Rb is a hydrogen atom, a hydroxy or C1-3-alkyl group:
By reacting a compound of general formula
Raxe2x80x94Axe2x80x94Hetxe2x80x94Bxe2x80x94Arxe2x80x94C(xe2x95x90NH)xe2x80x94Z1,xe2x80x83xe2x80x83(II)
optionally formed in the reaction mixture, wherein:
A, B, Ar, Het and Ra are as hereinbefore defined and
Z1 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with an amine of general formula
H2Nxe2x80x94Rbxe2x80x2xe2x80x83xe2x80x83(III)
wherein
Rbxe2x80x2 denotes a hydrogen atom or a hydroxy or C1-3-alkyl group.
The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxane at temperatures between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures between 20xc2x0 C. and 120xc2x0 C., with a compound of general formula III or with a corresponding acid addition salt such as ammonium carbonate, for example.
A compound of general formula II may be obtained, for example, by reacting a compound of general formula I wherein E denotes a cyano group, with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0xc2x0 C. and 50xc2x0 C., but preferably at 20xc2x0 C., or a corresponding nitrile with hydrogen sulfide, appropriately in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the resulting thioamide with a corresponding alkyl or aralkyl halide.
b. In order to prepare a compound of general formula I wherein the Raxe2x80x94Axe2x80x94 group and E are as hereinbefore defined, with the proviso that the Raxe2x80x94Axe2x80x94 group contains a carboxy group and E as hereinbefore defined or that the Raxe2x80x94Axe2x80x94 group is as hereinbefore defined and E denotes an NH2xe2x80x94C(xe2x95x90NH)xe2x80x94 group, or that the Raxe2x80x94Axe2x80x94 group contains a carboxy group and E denotes an NH2xe2x80x94C(xe2x95x90NH)xe2x80x94 group:
Converting a compound of general formula
Raxe2x80x2xe2x80x94Axe2x80x94Hetxe2x80x94Bxe2x80x94Arxe2x80x94Cxe2x80x94Exe2x80x2,xe2x80x83xe2x80x83(IV)
wherein
A, B, Ar and Het are as hereinbefore defined and
the Raxe2x80x2xe2x80x94Axe2x80x94 group and Exe2x80x2 have the meanings given for the Raxe2x80x94Axe2x80x94 group and E hereinbefore, with the proviso that the Raxe2x80x2xe2x80x94Axe2x80x94 group contains a group which may be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and E is as hereinbefore defined or Exe2x80x2 denotes a group which may be converted into an NH2xe2x80x94C(xe2x95x90NH)xe2x80x94 group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and the Raxe2x80x2xe2x80x94Axe2x80x94 group has the meanings given for the Raxe2x80x94Axe2x80x94 group hereinbefore or the Raxe2x80x2xe2x80x94Axe2x80x94 group contains a group which may be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and Exe2x80x2 denotes a group which may be converted into an NH2xe2x80x94C(xe2x95x90NH)xe2x80x94 group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
is converted by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of general formula I, wherein the Raxe2x80x2xe2x80x94Axe2x80x94 group and E are as hereinbefore defined, with the proviso that the Raxe2x80x2xe2x80x94Axe2x80x94 group contains a carboxy group and E is as hereinbefore defined or the Raxe2x80x2xe2x80x94Axe2x80x94 group has the meanings given above and E denotes an NH2xe2x80x94C(xe2x95x90NH)xe2x80x94 group or the Raxe2x80x94Axe2x80x94 group contains a carboxy group and E denotes an NH2xe2x80x94C(xe2x95x90NH)xe2x80x94 group.
Examples of groups which may be converted into a carboxy group include a carboxyl group protected by a protecting group and the functional derivatives thereof, e.g., the unsubstituted or substituted amides, esters, thioesters, trimethylsilylesters, orthoesters or iminoesters which may conveniently be converted into a carboxyl group by hydrolysis,
the esters thereof with tertiary alcohols, e.g., the tert-butylester, which are conveniently converted into a carboxyl group by treatment with an acid or by thermolysis, and
the esters thereof with aralkanols, e.g., the benzylester, which are conveniently converted into a carboxyl group by hydrogenolysis.
The hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between xe2x88x9210xc2x0 C. and 120xc2x0 C., e.g., at temperatures between room temperature and the boiling temperature of the reaction mixture.
If the Raxe2x80x2xe2x80x94Axe2x80x94 group and/or Exe2x80x2 in a compound of formula IV contains the tert-butyl or tert-butyloxycarbonyl group, for example, these may also be cleaved by treating with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane, preferably at temperatures between xe2x88x9210xc2x0 C. and 120xc2x0 C., e.g., at temperatures between 0C and 60xc2x0 C., or thermally optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic quantity of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid, or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g., at temperatures between 40xc2x0 C. and 120xc2x0 C.
If the Raxe2x80x2xe2x80x94Axe2x80x94 group and/or Exe2x80x2 in a compound of formula IV contains the benzyloxy or benzyloxycarbonyl group, for example, these may also be cleaved by hydrogenolysis in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane, or dimethylformamide, preferably at temperatures between 0xc2x0 C. and 50xc2x0 C., e.g., at room temperature, under a hydrogen pressure of 1 to 5 bar.
c. In order to prepare a compound of general formula I wherein the Raxe2x80x94Axe2x80x94 group contains one of the ester groups mentioned in the definition of the Raxe2x80x94Axe2x80x94 group hereinbefore:
Reaction of a compound of general formula
Raxe2x80x3xe2x80x94Axe2x80x94Hetxe2x80x94Bxe2x80x94Arxe2x80x94E,xe2x80x83xe2x80x83(V)
wherein
B, E, Ar, and Het are as hereinbefore defined, and
the Raxe2x80x3xe2x80x94Axe2x80x94 group has the meanings given for the Raxe2x80x94Axe2x80x94 group hereinbefore, with the proviso that the Raxe2x80x3xe2x80x94Axe2x80x94 group contains a carboxyl group or a group which may be converted into a corresponding ester group by means of an alcohol,
with an alcohol of general formula
HOxe2x80x94R7xe2x80x83xe2x80x83(VI)
wherein
R7 is the alkyl moiety of one of the above-mentioned groups which may be cleaved in vivo, with the exception of the R6xe2x80x94COxe2x80x94Oxe2x80x94(R5CRa)xe2x80x94 group for a carboxyl group, or with the formamide acetals thereof;
or with a compound of general formula
Z2xe2x80x94R8xe2x80x83xe2x80x83(VII)
wherein
R8 denotes the alkyl moiety of one of the above-mentioned groups which may be cleaved in vivo, with the exception of the R6xe2x80x94COxe2x80x94Oxe2x80x94(R5CR6)xe2x80x94 group for a carboxyl group, and Z2 denotes a leaving group such as a halogen atom, e.g., a chlorine or bromine atom.
The reaction with an alcohol of general formula VI is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, or dioxane, but preferably in an alcohol of general formula VI, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g., in the presence of isobutylchloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-thionyldiimidazole, triphenylphosphine/carbon tetrachloride, or triphenylphosphine/diethylazodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyldiisopropylamine, or N,N-dimethylaminopyridine, conveniently at temperatures between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures between 0xc2x0 C. and 80xc2x0 C.
With a compound of general formula VII the reaction is usefully carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide, or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyldiisopropylamine or N-methylmorpholine, which may act as solvent at the same time, or optionally in the presence of silver carbonate or silver oxide at temperatures between xe2x88x9230xc2x0 C. and 100xc2x0 C., but preferably at temperatures between xe2x88x9210xc2x0 C. and 80xc2x0 C.
d. In order to prepare a compound of general formula I wherein Rb denotes a group which may be cleaved in vivo:
Reacting a compound of general formula
Raxe2x80x94Axe2x80x94Hetxe2x80x94Bxe2x80x94Arxe2x80x94C(xe2x95x90NH)xe2x80x94NH2xe2x80x83xe2x80x83(VIII)
wherein
Ra, A, Het, B, and Ar are as hereinbefore defined, with a compound of general formula
Z2xe2x80x94R5xe2x80x83xe2x80x83(IX)
wherein
R5 denotes a group which may be cleaved in vivo, and
Z2 denotes a nucleofugic leaving group such as a halogen atom, e.g., a chlorine, bromine, or iodine atom.
The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide, or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at temperatures between 20xc2x0 C. and the boiling temperature of the solvent used.
With a compound of general formula IX, wherein Z2 denotes a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide, or dimethylsulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert-butoxide, or N-ethyldiisopropylamine at temperatures between 0xc2x0 C. and 60xc2x0 C.
e. In order to prepare a compound of general formula I wherein B denotes an ethylene group, in which a methylene group is replaced by a sulfinyl or sulfonyl group:
Oxidation of a compound of general formula
Raxe2x80x94Axe2x80x94Hetxe2x80x94Bxe2x80x2xe2x80x94Arxe2x80x94Exe2x80x83xe2x80x83(X)
wherein
A, E, Ar, Het, and Ra are as hereinbefore defined, and
Bxe2x80x2 denotes an ethylene group, wherein a methylene group is replaced by a sulfenyl or sulfinyl group.
The oxidation is preferably carried out in a solvent or mixture of solvents, e.g., in water, water/pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid/acetic anhydride, dilute sulfuric acid, or trifluoroacetic acid, and depending on the oxidizing agent used, at temperatures between xe2x88x9280xc2x0 C. and 1 00xc2x0 C.
In order to prepare a corresponding sulfinyl compound of general formula I oxidation is conveniently carried out with one equivalent of the oxidizing agent used, e.g., with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid, or formic acid at 0xc2x0 C. to 20xc2x0 C., or in acetone at 0xc2x0 C. to 60xc2x0 C., with a peracid such as performic acid in glacial acetic acid, or trifluoroacetic acid at 0xc2x0 C. to 50xc2x0 C., or with m-chloroperbenzoic acid in methylene chloride, chloroform, or dioxane at xe2x88x9220xc2x0 C to 80xc2x0 C., with sodium metaperiodate in aqueous methanol, or ethanol at xe2x88x9215xc2x0 C. to 25xc2x0 C., with bromine in glacial acetic acid, or aqueous acetic acid, optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert-butylhypochlorite in methanol at xe2x88x9280xc2x0 C. to xe2x88x9230xc2x0 C., with iodobenzodichloride in aqueous pyridine at 0xc2x0 C. to 50xc2x0 C., with nitric acid in glacial acetic acid at 0xc2x0 C. to 20xc2x0 C., with chromic acid in glacial acetic acid, or in acetone at 0xc2x0 C. to 20xc2x0 C. and with sulfuryl chloride in methylene chloride at xe2x88x9270xc2x0 C., the resulting thioether chlorine complex is conveniently hydrolyzed with aqueous ethanol.
In order to prepare a sulfonyl compound of general formula I, oxidation is carried out starting from a corresponding sulfinyl compound, conveniently with one or more equivalents of the oxidizing agent used, or starting from a corresponding sulfenyl compound, conveniently with two or more equivalents of the oxidizing agent used, e.g., with hydrogen peroxide in glacial acetic acid/acetic anhydride, trifluoroacetic acid, or in formic acid at 20 to 100xc2x0 C., or in acetone at 0 to 60xc2x0 C., with a peracid such as performic acid, or with m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride, or chloroform at temperatures between 0xc2x0 C. and 60xc2x0 C., with nitric acid in glacial acetic acid at 0C to 20xc2x0 C., with chromic acid, or potassium permanganate in glacial acetic acid, water/sulfuric acid, or in acetone at 0xc2x0 C. to 20xc2x0 C. Thus, by carrying out oxidation, for example, starting from a corresponding sulfenyl compound, preferably in methylene chloride, by treating with a corresponding amount of m-chloroperbenzoic acid at temperatures between 20xc2x0 C. and the reflux temperature of the reaction mixture, a corresponding sulfonyl compound of general formula I is obtained which may still contain a small amount of the corresponding sulfinyl compound.
f. In order to prepare a compound of general formula I wherein E is a cyano group and B is an ethylene group in which a methylene group linked either to group Het or to Ar is replaced by an oxygen or sulfur atom or by a sulfinyl, sulfonyl, carbonyl, or xe2x80x94NR1xe2x80x94 group:
Reacting a compound of general formula
Raxe2x80x94Axe2x80x94Hetxe2x80x94Uxe2x80x83xe2x80x83(XI)
with a compound of general formula
Vxe2x80x94Arxe2x80x94CNxe2x80x83xe2x80x83(XII)
wherein
Ra, A, Ar, and Het are as hereinbefore defined,
one of the groups U or V denotes an HOxe2x80x94, HSxe2x80x94, HOSOxe2x80x94, HOSO2xe2x80x94, or HNR1xe2x80x94 group, and the other group denotes a Z3CH2xe2x80x94 group, wherein R1 is as hereinbefore defined, and Z3 denotes a nucleofugic leaving group such as a halogen atom, e.g., a chlorine, bromine, or iodine atom.
The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide, or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20xc2x0 C. and the boiling temperature of the solvent used.
g. In order to prepare a compound of general formula I, wherein E is a cyano group and Ra denotes an R2NR3xe2x80x94 group:
Reacting a compound of general formula
Hxe2x80x94Axe2x80x94Hetxe2x80x94Bxe2x80x94Arxe2x80x94CNxe2x80x83xe2x80x83(XIII)
wherein
A, B, Het, and Ar are as hereinbefore defined, with an amine of general formula 
wherein
R2 and R3 are as hereinbefore defined, or with the reactive derivatives thereof.
The reaction of an acid of general formula XIII is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, or dioxane or in a corresponding amine of general formula III, optionally in the presence of a dehydrating agent, e.g., in the presence of isobutylchloroformate, tetraethylorthocarbonate, trimethylorthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetraethylammonium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetraethylammonium tetrafluoroborate/1-hydroxybenzotriazole, N,Nxe2x80x2-carbonyldiimidazole, or triphenylphosphine/carbon tetrachloride and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine, or triethylamine, conveniently at temperatures between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures between 0xc2x0 C. and 100xc2x0 C.
The reaction of a corresponding reactive compound of general formula XIII such as the esters, imidazolides or halides thereof with an amine of general formula XIV is preferably carried out in a corresponding amine as solvent, optionally in the presence of another solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine, or N-methylmorpholine at temperatures between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures between 50xc2x0 C. and 100xc2x0 C.
h. In order to prepare a benzimidazolyl, benzothiazolyl, or benzoxazolyl compound of general formula I wherein B denotes an ethylene group:
Reacting a compound of general formula 
wherein
Ra, A, and Y are as hereinbefore defined, with a compound of general formula
HOxe2x80x94COxe2x80x94CH2CH2xe2x80x94Arxe2x80x94Exe2x80x83xe2x80x83(XVI)
wherein
Ar and E are as hereinbefore defined, or with the reactive derivatives thereof.
The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, or dioxane, optionally in the presence of a dehydrating agent, e.g., in the presence of isobutylchloroformate, tetraethylorthocarbonate, trimethylorthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole, N,Nxe2x80x2-carbonyldiimidazole, or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine, or triethylamine, appropriately at temperatures between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures between 0xc2x0 C. and 100xc2x0 C.
The reaction of a corresponding reactive compound of general formula XVI such as the esters, imidazolides or halides thereof with an amine of general formula XV is preferably carried out in a solvent such as methylene chloride, ether, or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine, or N-methylmorpholine, which may simultaneously be used as solvents, at temperatures between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures between 50xc2x0 C. and 100xc2x0 C.
i. In order to prepare a quinoxalin-2-one compound of the general formula:
Reacting a compound of general formula 
wherein
Ra, R1, and A are as hereinbefore defined, with a compound of general formula
HOxe2x80x94COxe2x80x94COCH2xe2x80x94Arxe2x80x94Exe2x80x83xe2x80x83(XVIII)
wherein
Ar and E are as hereinbefore defined, or with the reactive derivatives thereof.
The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, ethanol, or dioxane, optionally in the presence of a dehydrating agent, e.g., in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorusxe2x80x94trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole, N,Nxe2x80x2-carbonyldiimidazole, or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine, or triethylamine, appropriately at temperatures of between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures of between 0xc2x0 C. and 100xc2x0 C.
However, it is particularly preferred to carry out the reaction with a corresponding reactive compound of general formula XVIII such as the esters, imidazolides or halides thereof with an amine of general formula XVII in a solvent such as methylene chloride, ether, ethanol, or tetrahydrofuran and optionally in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine, or N-methylmorpholine, which may simultaneously serve as solvent, at temperatures of between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures of between 50xc2x0 C. and 100xc2x0 C.
j. In order to prepare a compound of general formula I wherein R2 denotes a C1-4-alkyl group substituted by an alkylsulfonylaminocarbonyl group:
Reacting a compound of general formula 
wherein
R3, A, B, E, and Het are as hereinbefore defined, and
R2xe2x80x2 denotes a C1-4-alkyl group substituted by a carboxy group, or the reactive derivatives thereof, with a salt of a compound of general formula
C1-3-Alkyl-SO2xe2x80x94NH2xe2x80x83xe2x80x83(XX)
The reaction is preferably carried out with a corresponding reactive compound of general formula IXX such as the esters, imidazolides, or halides thereof with a salt of a compound of general formula XX, preferably with an alkali metal salt thereof such as a sodium salt, in a solvent such as methylene chloride, ether, ethanol, tetrahydrofuran, or dimethylformamide at temperatures between 0xc2x0 C. and 150xc2x0 C., preferably at temperatures of between 50xc2x0 C. and 100xc2x0 C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino, or imino groups may be protected during the reaction by means of conventional protecting groups which are removed by cleaving after the reaction.
For example, the protecting group for a hydroxy group may be the trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl, or tetrahydropyranyl group,
the protecting group for a carboxyl group may be the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl, or tetrahydropyranyl group, and
the protecting group for an amino, alkylamino, or imino group may be the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, or 2,4-dimethoxybenzyl group and for the amino group the phthalyl group may also be considered.
The optional subsequent cleaving of a protecting group may, for example, be carried out hydrolytically in an aqueous solvent, e.g., in water, isopropanol/water, tetrahydrofuran/water, or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid, or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide or by ether cleaving, e.g., in the presence of iodotrimethylsilane, at temperatures between 0xc2x0 C. and 100xc2x0 C., preferably at temperatures between 10xc2x0 C. and 50xc2x0 C.
However, a benzyl, methoxybenzyl, or benzyloxycarbonyl group may for example be cleaved hydrogenolytically, e.g., using hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone, or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0xc2x0 C. and 50xc2x0 C., but preferably at room temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.
A methoxybenzyl group may also be cleaved in the presence of an oxidizing agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile, or acetonitrile/water at temperatures between 0xc2x0 C. and 50xc2x0 C., but preferably at room temperature.
However, a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, or ether.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine, or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water, or dioxane, at temperatures between 20xc2x0 C. and 50xc2x0 C.
An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis(triphenylphosphine)palladium(0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone, at temperatures between 0xc2x0 C. and 100xc2x0 C., preferably at room temperature and under inert gas, or by treating with a catalytic amount of tris(triphenylphosphine)rhodium(I) chloride, in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane, at temperatures between 20xc2x0 C. and 70xc2x0 C.
The compounds of general formulae II to XX used as starting materials, some of which are known from the literature, may be obtained by methods known from the literature and moreover their production is described in the Examples.
Thus, for example, a compound of general formula II is obtained by reacting a corresponding nitrile which in turn is conveniently obtained by processes f to h, with a corresponding thio or alcohol in the presence of hydrogen chloride or bromide.
A compound of general formulae IV, V, VIII, X, and IXX used as starting material is conveniently obtained according to a process of the present invention.
A starting compound of general formula XI in which U denotes a halomethyl group is conveniently obtained by cyclization of a corresponding ester which is substituted in the o-position by a suitable halogen atom and a methoxyacetamido group, to form a corresponding bicyclic 2-alkoxymethyl compound, optionally subsequent hydrolysis and optionally subsequent amidation of a resulting carboxylic acid with a corresponding amine, converting the alkoxymethyl compound thus obtained into the corresponding halomethyl compound, which can if necessary be subsequently converted into the desired compound by means of a suitable compound. If the cyclization is carried out with a suitable carbonic acid derivative, a starting compound of general formula XI is obtained wherein U denotes a hydroxy, mercapto, or amino group.
A starting compound of general formula XIII is obtained by cyclization of a corresponding o-disubstituted ester, followed by saponification of the resulting ester and subsequent amidation of the carboxylic acid thus obtained with a corresponding amine.
Furthermore, an imidazopyridine substituted in the 5-position by a methyl group and obtained by cyclization can be converted, via the corresponding N-oxide, into the corresponding hydroxymethyl compound which is converted by oxidation into the desired carboxylic acid of general formula XIII.
The compounds of general formulae III, VI, VII, IX, and XII used as starting materials are obtained by conventional methods, for example by reducing an aromatic ester substituted in the opposition by an optionally substituted amino group and a nitro group, and optionally subsequent cyclization of the resulting o-diamino compound with a corresponding carboxylic acid.
Furthermore, the compounds of general formula I obtained may be separated into their enantiomers and/or diastereomers.
Thus, for example, the compounds of general formula I obtained which occur in racemate form may be separated by methods known per se (see N. L. Allinger and E. L. Eliel in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes, and compounds of general formula I having at least 2 asymmetric carbon atoms may be separated on the basis of their physical-chemical differences using known methods, e.g., by chromatography and/or fractional crystallization, into the diastereomers thereof, which, if they occur in racemic form, may subsequently be separated into the enantiomers as mentioned above.
The separation of enantiomers is preferably effected by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with an optically active substance, especially acids and the activated derivatives thereof or alcohols, which forms salts or derivatives such as, e.g., esters or amides with the racemic compound, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g., on the basis of their different solubilities, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are, for example, the D- and L-forms of tartaric acid, and dibenzoyltartaric acid, di-otolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, and quinaldic acid. Examples of optically active alcohols include for example (+)- or (xe2x88x92)-menthol and examples of optically active acyl groups in amides include, for example, (+)- or (xe2x88x92)-menthyloxycarbonyl.
Moreover, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of suitable acids include for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
In addition, the new compounds of formula I thus obtained, if they contain a carboxyl group, may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, more particularly, for pharmaceutical use, into the physiologically acceptable salts thereof. Examples of suitable bases include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.
As already mentioned, the new compounds of general formula I and the salts thereof have valuable properties. Thus, the compounds of general formula I wherein E denotes a cyano group are valuable intermediate products for preparing the other compounds of general formula I and the compounds of general formula I wherein E denotes an RbNHxe2x80x94C(xe2x95x90NH)xe2x80x94 group and the tautomers, the stereoisomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly a thrombin-inhibiting effect, an effect of prolonging the thrombin time and an inhibitory effect on related serine proteases such as e.g., trypsin, urokinase factor VIIa, factor Xa, factor IX, factor XI, and factor XII, whilst a few compounds such as for example the compound of Example 16 simultaneously also have a slight inhibitory effect on thrombocyte aggregation.
For example, the following compounds:
A is 2-[N-(4-amidinophenyl)aminomethyl]benzthiazole-5-carboxylic acid-N-phenyl-N-(2-carboxyethyl)amide;
B is 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-hydroxycarbonylpropyl)amide;
C is 1-methyl-2-[(4-amidinophenyl)oxymethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(hydroxycarbonylmethyl)amide;
D is 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-hydroxycarbonylethyl)amide;
E is 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(hydroxycarbonylmethyl)amide;
F is 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-[2-(1H-tetrazol-5-yl)ethyl]amide; and
G is 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)amide,
were investigated as follows for their effects on thrombin time:
Materials: plasma, from human citrated blood.
Test thrombin (bovine), 30 U/mI, Behring Werke, Marburg
Diethylbarbiturate acetate buffer, ORWH 60/61, Behring Werke, Marburg
Biomatic B10 coagulometer, Sarstedt
Method
The thrombin time was determined using a Biomatic B10 coagulometer made by Messrs. Sarstedt. As the test substance, 0.1 ml of human citrated plasma and 0.1 ml diethylbarbiturate buffer (DBA buffer) were added to the test strip prescribed by the manufacturer. The mixture was incubated for one minute at 37xc2x0 C. The clotting reaction was started by the addition of 0.3 U test thrombin in 0.1 ml DBA buffer. The time is measured using the apparatus from the addition of the thrombin up to the clotting of the mixture. Mixtures to which 0.1 ml of DBA buffer were added were used as the controls.
According to the definition, a dosage-activity curve was used to determine the effective concentration of the substance, i.e., the concentration at which the thrombin time is double compared with the control.
The Table which follows contains the results found:
By way of example, no acute toxic side effects were observed when compounds A, D, E, and G were administered to rats in doses of up to 10 mg/kg i.v. The compounds are thus well tolerated.
In view of their pharmacological properties, the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, for preventing coronary thrombosis, stroke and the occlusion of shunts or stents. In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with rt-PA or streptokinase, for preventing long-term restenosis after PT(C)A, for preventing metastasis and the growth of clot-dependent tumors and fibrin-dependent inflammatory processes.
The dosage required to achieve such an effect is appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and 0.1 to 50 mg/kg, preferably 0.3 to 30 mg/kg by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g., with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, or suppositories.
The Examples which follow are intended to illustrate the invention:
Preliminary Remarks
Unless otherwise specified, the Rf values were always determined using polygram silica gel plates produced by Messrs. E. Merck of Darmstadt. The EKA mass spectra (electrospray mass spectra of cations) are described, for example, in xe2x80x9cChemie unserer Zeitxe2x80x9d 6, 308-316 (1991).